Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor - Role of oxidative stress
Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor - Role of oxidative stress
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DOI：
10.1161/hypertensionaha.107.091058
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发表时间：
2007-11-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Nagase, Miki;Matsui, Hiromitsu;Fujita, Toshiro
醛固酮与蛋白尿和慢性肾脏病的发病机制有关。我们之前证明了血清醛固酮升高在代谢综合征大鼠模型 SHR/NDmcr-cp (SHR/cp) 早期肾病中的作用。在本研究中，我们研究了盐负荷对 SHR/cps 肾损伤的影响，并探讨了其潜在机制。 SHR/cps 喂养高钠饮食 4 周后出现严重高血压、大量蛋白尿和晚期肾脏病变。高盐还会加重肾小球足细胞损伤。令人惊讶的是，选择性盐皮质激素受体 (MR) 拮抗剂依普利农显着改善了 SHR/cps 中盐诱导的蛋白尿和肾损伤。虽然盐负荷降低了循环醛固酮，但它增加了肾脏中的核 MR 和醛固酮效应激酶 Sgk1 的表达。在盐负载的 SHR/cps 的肾脏中，转化生长因子-β 1 和纤溶酶原激活物抑制剂-1 的基因表达也增强，而依普利农完全抑制了这些损伤标志物。为了澄清醛固酮减少和盐引起的 MR 信号增强之间的差异，我们进一步研究了氧化应激的作用，氧化应激是介导盐诱导的组织损伤的假定关键因素。有趣的是，抗氧化剂 Tempol 减弱了盐诱发的 MR 上调和 Sgk1 诱导，并减轻了蛋白尿和肾脏组织学异常，表明氧化应激参与了盐诱发的 MR 激活。盐引起的 MR 激活并不归因于血清皮质酮增加或 11β-羟基类固醇脱氢酶 2 型活性降低。总之，钠负荷加剧了代谢综合征大鼠的蛋白尿和肾损伤。盐减少了循环醛固酮，但至少部分通过诱导氧化应激引起肾 MR 激活，而依普利农有效改善了肾病。
Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta 1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11 beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.